Project Summary The present application ?Novel Treatment for Posttraumatic Stress Disorder? addresses the critical need for more efficacious treatments for posttraumatic stress disorder (PTSD). The excitatory neurotransmitter, glutamate, activates a key neural signaling cascade upon a trauma experience. In this activation, glutamate binds to and activates the NMDA receptor, a glutamate receptor subtype. Binding and activation triggers the formation of a complex at the receptor and leads to activation of the enzyme neuronal nitric oxide synthase (nNOS) and a concomitant increase in the production of the signaling molecule nitric oxide (NO). These events trigger aberrant synaptic plasticity that is implicated in the initiation and maintenance of PTSD. Postsynaptic density protein 95 (PSD95) targets nNOS to the NMDA receptor facilitating the formation of this signaling complex. PSD95 is therefore, required for NMDA receptor activation of nNOS. Lai, Anagin co-founder and principal investigator for this project, first showed that the small molecule, IC87201, disrupts the functional protein-protein interaction between nNOS and PSD95 in vitro and attenuates NMDA receptor dependent hyperalgesia in vivo. Anagin, an Indiana-based small business and its preclinical team at Indiana University, led by Dr. Shekhar (co-founder of Anagin), has demonstrated that IC87201 and a related analog, ZL006, block the long-term encoding of conditioned fear even after a fear conditioning session has occurred (i.e. post- trauma). Unlike NMDA receptor antagonists, these protein interaction inhibitors are efficacious in suppressing PTSD-like symptoms in a well-established preclinical model without producing motor or memory impairment. Thus, disruption of signal compartmentalization represents an innovative approach to develop novel treatments for anxiety disorders with fewer side-effects. In Anagin's successful SBIR Phase I studies, the team established positive structural-activity-relationship and demonstrated oral efficacy of its first-generation lead and identified a promising new chemical series. The goal of this Phase II SBIR is to deliver an orally available drug candidate and initiate IND-enabling studies delineated through two specific aims. Aim 1: Perform lead optimization studies to select a Drug Development Candidate. Aim 2: Validate the Drug Development Candidate in IND-enabling studies. A traditional drug medicinal chemistry approach will be used to design and develop novel analogs with improved pharmacokinetic properties and potency compared to the parent compounds. Anagin anticipates completion of initial IND-enabling studies at the end of the grant period. The development of effective pharmacotherapies with novel chemical structures that possess limited side-effect profiles is expected to drive down escalating health care costs and alleviate unnecessary suffering in PTSD patients. The ultimate goal is an FDA IND submission of a drug candidate for Phase I clinical trials in PTSD or anxiety disorders.